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original reports

Metachronous Contralateral Testicular Cancer in the Cisplatin Era: A Population-Based

Cohort Study

Ragnhild Hellesnes, MD1,2; TorAge Myklebust, PhD˚ 3,4; Roy M. Bremnes, MD, PhD1,2; ´Asa Karlsdottir, MD, PhD5; Øivind Kvammen, MD6; Helene F. S. Negaard, MD, PhD7; Torgrim Tandstad, MD, PhD8,9; Tom Wilsgaard, PhD10; Sophie D. Fossa, MD, PhD˚ 4,7,11; and Hege S. Haugnes, MD, PhD1,2

abstract

PURPOSE It is hypothesized that cisplatin-based chemotherapy (CBCT) reduces the occurrence of meta-

chronous contralateral (second) germ cell testicular cancer (TC). However, studies including treatment details are lacking. The aim of this study was to assess the second TC risk, emphasizing the impact of previous TC treatment.

PATIENTS AND METHODSBased on the Cancer Registry of Norway, 5,620 men were diagnosed withfirst TC between 1980 and 2009. Treatment data regarding TC were retrieved from medical records. Cumulative in- cidences of second TC were estimated, and standardized incidence ratios were calculated. The effect of treatment intensity was investigated using Cox proportional hazard regression.

RESULTS Median follow-up was 18.0 years, during which 218 men were diagnosed with a second TC after median 6.2 years. Overall, the 20-year crude cumulative incidence was 4.0% (95% CI, 3.5 to 4.6), with lower incidence after chemotherapy (CT) (3.2%; 95% CI, 2.5 to 4.0) than after surgery only (5.4%; 95% CI, 4.2 to 6.8).

The second TC incidence was also lower for those age$30 years (2.8%; 95% CI, 2.3 to 3.4) atfirst TC diagnosis than those age,30 years (6.0%; 95% CI, 5.0 to 7.1). Overall, the second TC risk was 13-fold higher compared with the risk of developing TC in the general male population (standardized incidence ratio, 13.1; 95% CI, 11.5 to 15.0). With surgery only as reference, treatment with CT significantly reduced the second TC risk (hazard ratio [HR], 0.55). For each additional CBCT cycle administered, the second TC risk decreased significantly after three, four, and more than four cycles (HRs, 0.53, 0.41, and 0.21, respectively).

CONCLUSIONAge atfirst TC diagnosis and treatment intensity influenced the second TC risk, with significantly reduced risks after more than two CBCT cycles.

J Clin Oncol 39:308-318. © 2020 by American Society of Clinical Oncology

INTRODUCTION

After being diagnosed with a primary germ cell tes- ticular cancer (TC), the estimated 15-20–year cu- mulative incidence of a metachronous contralateral (second) TC is 1.9%-3.9%.1-4Standardized incidence ratios (SIRs), comparing the incidence of second TC with the incidence of TC in the general population, range from 12.4 to 35.7.1-7Treatment of the second TC will usually involve a surgical castration, leading to infertility and lifelong dependency of testosterone substitution.8,9 From personal experience, many tes- ticular cancer survivors (TCS) with unilateral disease fear losing their remaining testicle.

Shared etiological factors for thefirst and second TC, hypothesized to cause the testicular dysgenesis syn- drome, represent a likely explanation for the increased incidence of a second TC.10,11Young age at diagnosis of thefirst TC is associated with the increased risk of developing a second TC.1-4,12The results are, however,

inconclusive regarding the effect offirst TC histology and subsequent second TC risk.1,4,7,13,14

The introduction of cisplatin in the late 1970s led to dramatically improved survival of patients with meta- static TC.15,16Cisplatin-based chemotherapy (CBCT) is hypothesized to reduce or delay the incidence of a metachronous contralateral TC. However, the existing literature lacks TC treatment details, if based on public registries,1,2 involves populations screened for germ cell neoplasia in situ (GCNIS),12,17or includes patients treated in the precisplatin era.3-5

Andreassen et al2investigated the risk for metachro- nous contralateral TC in 7,102 TCS in Norway treated during 1953-2007. They found a 50% risk reduction for a second TC in men treated for metastatic com- pared with localized disease only for those treated after 1980, implying that this risk reduction was related to the introduction of CBCT. They emphasized that the greatest limitation of their study was the lack of TC

ASSOCIATED CONTENT See accompanying editorial on page265 Appendix

Author afliations and support information (if applicable) appear at the end of this article.

Accepted on October 21, 2020 and published at ascopubs.org/journal/

jcoon December 23, 2020: DOIhttps://doi.

org/10.1200/JCO.20.

02713

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treatment details. Furthermore, Fossa et al˚ 1conducted a large register-based study involving 29,515 TCS from the United States. They concluded that a potential dose- response relationship between cisplatin and eradication of germ cell carcinoma in situ should be investigated in future clinical studies.

The aim of this population-based study was to assess the risk of developing a metachronous contralateral TC, with emphasis on the impact of previous TC treatment including CBCT, in a national cohort with complete data on TC treatment.

PATIENTS AND METHODS Study Cohort and Design

The Cancer Registry of Norway (CRN) identified men di- agnosed with histologically verified primary germ cell TC from January 1, 1980, to December 31, 2009.18 Major exclusion criteria included age,16 years at TC diagnosis, a prior malignancy, extragonadal germ cell cancer, and synchronous contralateral TC or death within 2 months of follow-up (Appendix Fig A1, online only). Metachronous TC was defined as a second germ cell TC diagnosed .2 months after the primary TC.

After exclusions, this historical prospective cohort study consisted of 5,620 patients with TC. Details re- garding disease stage, histology, and TC treatment for first and second TCs, including relapse treatment, were retrieved from medical records. Linkage with the CRN updated through December 31, 2018, was done to ensure complete information on the incidence of second TC.

The study was approved by the Regional Committee for Medical and Health Research Ethics and the Data Pro- tection Authorities at the University Hospital of North Norway. Passive consent from all eligible men still alive was obtained through a study information letter with the pos- sibility to withdraw from participation, after which 23 (0.38%) men declined participation.

Staging, Treatment, and Treatment Groups

TC was staged according to the Royal Marsden Hospital staging system.19 During the study period, the treatment principles for TC changed as previously described.20 Ad- juvant radiotherapy (RT) for stage I seminoma has gradually been abandoned, and the number of CBCT cycles applied for metastatic disease has been reduced. The use of a risk- adapted surveillance strategy or one cycle of adjuvant CBCT (nonseminoma) or carboplatin (seminoma) for stage I disease has been implemented as recommended by the Swedish and Norwegian Testicular Cancer Group (SWENOTECA).21

Based on total treatment burden for thefirst TC, the cohort was divided into four treatment groups: surgery only (in- cluding surveillance n51,417; 25%), chemotherapy (CT, n52,450; 44%), RT (n51,543, 27%), and both CT and RT (CT1RT, n5210; 3.7%) (Table 1).

Statistical Methods

Continuous variables were presented with median and interquartile range (IQR), and categorical variables were presented with numbers and percent.

Follow-up was calculated from 2 months after diagnosis of thefirst TC until a diagnosis of a second TC, death, emi- gration, or December 31, 2018, whichever occurredfirst.

Treatment was analyzed as a time-varying covariate, achieved by splitting follow-up time at exact treatment dates for each treatment modality, to avoid immortal time bias.

The K-sample median test was used to test differences in median time to second TC among those developing a second TC, presented with two-sidedP-values.

The crude cumulative incidence of metachronous con- tralateral TC was estimated using the Aalen-Johansen estimator,22with death of any cause as a competing risk.

To compare the incidence of metachronous contralateral TC to the incidence of TC in the general population, SIRs were calculated. The estimates were obtained by dividing the number of metachronous contralateral TCs in the co- hort to the expected number of metachronous contralateral CONTEXT

Key Objective

Does cisplatin-based chemotherapy (CBCT) reduce the risk of a metachronous contralateral (second) testicular cancer (TC)?

Knowledge Generated

The overall 20-year cumulative incidence of second TC in a population-based cohort was 4%. Treatment with CBCT significantly reduced the second TC risk, with a stronger risk reduction for each additional CBCT cycle administered.

Older age at diagnosis offirst TC also reduced the risk.

Relevance

Our findings add important knowledge concerning the risk of second TC. Our results are important and appreciated information for patients with TC and healthcare personnel involved in TC treatment.

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TABLE 1. Patient Characteristics at First Primary TC Diagnosis

Characteristic Total at Risk (N55,620)

Individuals Without Second TC (n55,402)

Individuals Developing Second TC (n5218)

Decade ofrst TC diagnosis

1980-1989 1,287 (23) 1,228 (23) 59 (27)

1990-1999 1,897 (34) 1,824 (34) 73 (34)

2000-2009 2,436 (43) 2,350 (43) 86 (39)

Follow-up, years, median (IQR)a 18.0 (12.0-25.5) 18.5 (12.5-25.8) 6.2 (3.3-10.6)b

Age at diagnosis, years, median (IQR) 33.0 (27.2-40.9) 33.3 (27.3-41.2) 28.7 (24.6-33.5)

Age at diagnosis, dichotomized, years

,30 2,124 (38) 1,999 (37) 125 (57)

$30 3,496 (62) 3,403 (63) 93 (43)

Histology

Seminoma 2,938 (52) 2,831 (52) 107 (49)

Nonseminoma 2,682 (48) 2,571 (48) 111 (51)

Initial disease stagec

I 3,942 (70) 3,766 (70) 176 (80)

Mk1/II 1,127 (20) 1,097 (20) 30 (14)

III 116 (2.1) 114 (2.1) 2 (1.0)

IV 435 (7.7) 425 (7.9) 10 (4.6)

Treatmentd

Surgery onlye 1,417 (25) 1,345f(25) 72 (33)

CT 2,450 (44) 2,379 (44) 71 (32)

RT 1,543 (27) 1,471 (27) 72 (33)

CT1RT 210 (3.7) 207 (3.8) 3 (1.4)

Cause ofrst-line CT

Adjuvant, CS I 843 (32) 811 (31) 32 (43)

Primary metastatic disease 1,538 (58) 1,502 (58) 36 (49)

Recurrence 279 (10) 273 (11) 6 (8.1)

First CT regimen

BEP-20 1,507 (57) 1,464 (57) 43 (58)

CVB 367 (14) 357 (14) 10 (13.5)

EP 241 (9.1) 237 (9.2) 4 (5.4)

Other CBCTg 184 (6.9) 180 (6.9) 4 (5.4)

Adjuvant carboplatinh 295 (11) 285 (11) 10 (13.5)

CEB 44 (1.6) 42 (1.6) 2 (2.7)

Otheri 22 (0.8) 21 (0.8) 1 (1.4)

No. of CBCT cyclesj

1 220 (9.5) 210 (9.3) 10 (16)

2 319 (14) 307 (14) 12 (20)

3 439 (19) 427 (19) 12 (20)

4 1,028 (44) 1,004 (44) 24 (39)

.4 320 (14) 317 (14) 3 (4.9)

RTrsteld

L-Fieldk 1,388 (79) 1,321 (79) 67 (89)

Para-aortal 267 (15) 260 (15) 7 (9.3)

(continued on following page)

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TC, given the incidence of TC in a comparable Norwegian male population, matched by 5-year age groups and cal- endar year of follow-up. Cumulative incidences and SIRs with respective 95% CIs were calculated for the whole cohort and stratified according to treatment groups, age at diagnosis, follow-up time, and histology.

The effect of treatment and histology on the second TC risk were evaluated using Cox proportional hazard re- gression models with time since diagnosis as time scale, the surgery-only group as reference, and adjusting for age at diagnosis.20Additionally, histology as a risk factor was investigated in a multivariable Cox regression model which included treatment. Cumulative CT doses were estimated based on the CT regimen and number of CT cycles. The Cox regression model was also used to evaluate the effect of age at diagnosis (dichotomized). A nonsignificant Schoenfeld test showed that the propor- tional hazard assumption was met for all analyses, except for cumulative doses (AppendixTable A1, online only)

and the dichotomized age variable (P5.049). For the latter, the proportional hazard assumption was judged to be met by visual inspection of a log-log survival plot. The results are presented as hazard ratios (HRs) with cor- responding 95% CIs andP-values.

Data were analyzed using Stata statistical software (version MP 16.1; STATA, College Station, TX). AP-value,.05 was considered significant.

RESULTS

Characteristics of the Total Study Cohort and the Metachronous TC Subcohort

The total study cohort consisted of 5,620 men with a median follow-up time of 18 years (IQR, 12.0-25.5) (Table 1). Median age at diagnosis was 33 years, 38%

were ,30 years, and 70% were diagnosed with stage I disease atfirst TC. Overall, 25% were treated with surgery only, and 44% were treated with CT atfirst TC.

TABLE 1. Patient Characteristics at First Primary TC Diagnosis (continued)

Characteristic Total at Risk (N55,620)

Individuals Without Second TC (n55,402)

Individuals Developing Second TC (n5218)

Supradiaphragmatic 13 (0.7) 12 (0.7) 1 (1.3)

Supra- and infradiaphragmaticl 21 (1.2) 21 (1.3) 0

Otherm 64 (3.6) 64 (3.8) 0

RT dose forrst RTeld, Gy

1-20 13 (0.7) 12 (0.7) 1 (1.3)

20-29 514 (29) 490 (29) 24 (32)

30-39 986 (56) 943 (56) 43 (57)

$40 240 (14) 233 (14) 7 (9.3)

NOTE. Data are presented as n (%), unless otherwise stated.

Abbreviations: BEP-20, bleomycin, etoposide, and cisplatin; CBCT, cisplatin-based chemotherapy; CEB, carboplatin, etoposide, and bleomycin; CS I, clinical stage I; CT, chemotherapy; CT1RT, combination of CT and RT; CVB, cisplatin, vinblastine, and bleomycin; EP, etoposide and cisplatin; Gy, gray; IQR, interquartile range; Mk1, marker positive; RT, radiotherapy; TC, testicular cancer.

aFollow-up until diagnosis of metachronous contralateral TC, death, emigration, or December 31, 2018, whichever occurredrst.

bThe longest time interval betweenrst TC and second TC was 27.1 years.

cAs described by Peckham et al.19

dBased on total treatment burden.

eThe surgery-only group included men followed with surveillance after orchiectomy (n51,167; 21%) and men who underwent additional retroperitoneal lymph node dissection without CT or RT (n5250; 4.4%).

fTwo men included in the surgery-only group were diagnosed with clinical stage IV. One refused treatment, and the other was no candidate for treatment.

They both died shortly (but.2 months) after diagnosis.

gOf which a total of 141 were dose-escalated CBCT.

hFifteen of the 295 men initially treated with adjuvant carboplatin were subsequently treated with CBCT and, as a consequence, analyzed according to the total number of CBCT cycles. Also, one person had RT in addition to carboplatin. Of the 279 men treated with adjuvant carboplatin monotherapy included in the Cox regression analysis, 273 received one cycle and 6 received two cycles.

iCarboplatin monotherapy in metastatic setting (n517), cyclophosphamide/adriamycin (n51), CAOS (actinomycin D, adriamycin, vincristine, cyclophosphamide) (n53), actinomycin D (n51).

jMay have received additional CT regimes, but these are not accounted for in this number. A total of 334 men received non-CBCT, which are not included here.

kL-Field or dogleg-eld. Also included in this category are 53 individuals who received RT of groin in addition to L-eld and two individuals who received a reversed Y-eld.

lSixteen of 21 individuals received infradiaphragmatic RT asrst RT-eld and a short while later received supradiaphragmatic RT.

mRT toward bone (n521), CNS (n521), abdominal residual masses (n516), intraoperative RT (n51), skin lesions (n51), nonspecied sites (n54).

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Overall, 218 (3.9%) men developed a metachronous contralateral TC after median 6.2 years (IQR, 3.3-10.6) (Table 1). Among these 218 men, median age atfirst TC diagnosis was 28.7 years, 57% were,30 years at diag- nosis offirst TC, and seminoma (49%) and nonseminoma (51%) histology of the first TC was equally distributed.

Furthermore, 80% were diagnosed with clinical stage I at first TC, and as treatment forfirst TC, 33% had surgery only and 32% received CT. Median time to second TC did not differ according to treatment (P5.55) or age at diagnosis of first TC (P5.10) (AppendixTable A2, online only).

The majority of the second TCs were seminomas (72%) (Appendix Table A3, online only). At diagnosis of the second TC, 84% had stage I disease and 53% were treated with surgery only.

Cumulative Incidences of Second TC

The overall crude cumulative second TC incidence was 4.0% (95% CI, 3.5 to 4.6) at 20 years (Fig 1A,Table 2). The second TC incidence was lower in those age$30 years at first TC diagnosis (2.8%; 95% CI, 2.3 to 3.4) than in those age,30 years (6.0%; 95% CI, 5.0 to 7.1) (Fig 1B). The second TC incidence was also lower after treatment with CT (3.2%; 95% CI, 2.5 to 4.0) and CT1RT atfirst TC (1.4%;

95% CI, 0.4 to 3.9) than after surgery only (5.4%; 95% CI, 4.2 to 6.8) or RT (4.5%; 95% CI, 3.6 to 5.6) (Fig 1C).

For those age ,30 years at first TC diagnosis, 20-year cumulative incidence after surgery only was 8.0% (95% CI, 5.8 to 10.6), and after CT, it was 4.8% (95% CI, 3.6 to 6.3) (Table 2). In comparison, for those age$30 years atfirst TC diagnosis, the second TC incidence was 3.2% (95% CI,

1 2 3 4 5 6 7 8 9 10

Cumulative Incidence, %

0 5 10 15 20 25 30

Follow-Up Time (years)

A

30 years

< 30 years

1 2 3 4 5 6 7 8 9 10

Cumulative Incidence, %

0 5 10 15 20 25 30

Follow-Up Time (years)

B

Surgery only RT

CT CT + RT

1 2 3 4 5 6 7 8 9 10

Cumulative Incidence, %

0 5 10 15 20 25 30

Follow-Up Time (years)

C

Nonseminoma Seminoma

1 2 3 4 5 6 7 8 9 10

Cumulative Incidence, %

0 5 10 15 20 25 30

Follow-Up Time (years)

D

FIG 1. Crude cumulative incidences of metachronous contralateral TC by follow-up time. (A) All patients (with 95% CI), (B) by age atrst TC, dichotomized (C) by treatment groups atrst TC, and (D) by histology atrst TC. In (A), the red line indicates the incidence of metachronous contralateral TC, and the blue area indicates the 95% CI. CT, chemotherapy; CT1RT, combination of CT and RT; RT, radiotherapy; TC, testicular cancer.

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2.1 to 4.6) after surgery only and 1.7% (95% CI, 1.1 to 2.7) after CT.

The second TC incidence did not differ according tofirst TC histology, with estimates of 3.8% (95% CI, 3.1 to 4.6) after seminoma and 4.3% (95% CI, 3.5 to 5.1) after non- seminoma (Fig 1D).

Risk of Second TC in Relation to the General Population Overall, the second TC risk was 13-fold higher compared with the risk of developing TC in the general population (SIR, 13.1; 95% CI, 11.5 to 15.0) (Table 3). The risk was lower after treatment with CT (SIR, 9.1; 95% CI, 7.2 to 11.5) and CT1RT (SIR, 8.6; 95% CI, 2.8 to 26.7) atfirst TC than

after surgery only (SIR, 16.3; 95% CI, 12.9 to 20.5) and RT (SIR, 17.7; 95% CI, 14.1 to 22.3). SIRs decreased with increasing age at diagnosis and was highest for those age 20-30 years (SIR, 14.0; 95% CI, 11.7 to 16.8.). The risk for a second TC was the highest within the first 5 years of follow-up after diagnosis of thefirst TC (SIR, 17.0; 95% CI, 13.7 to 21.2) and decreased with increasing follow-up time.

HRs for Second TC

With surgery only as the reference group, the second TC risk was significantly lower after treatment with CT atfirst TC (HR, 0.55; 95% CI, 0.40 to 0.76) (Table 4). A sensitivity analysis excluding those treated with CT other than CBCT TABLE 2. Cumulative Incidences of Metachronous Contralateral TC According to Treatment, Age, and Histology at First TC and Specied Follow-up Time

<5 years <10 years <15 years <20 years

Variable n % 95% CI n % 95% CI n % 95% CI n % 95% CI

Total 82 1.5 1.2 to 1.8 157 2.8 2.4 to 3.3 192 3.5 3.1 to 4.1 209 4.0 3.5 to 4.6

Age at diagnosis, years

,30 38 1.8 1.3 to 2.4 86 4.1 3.3 to 5.0 106 5.2 4.3 to 6.2 118 6.0 5.0 to 7.1

$30 44 1.3 0.9 to 1.7 71 2.0 1.6 to 2.6 86 2.6 2.1 to 3.1 91 2.8 2.3 to 3.4

Treatment, all patients

Surgery onlya 24 1.6 1.1 to 2.4 52 3.6 2.8 to 4.7 62 4.5 3.5 to 5.7 68 5.4 4.2 to 6.8

CT 25 1.0 0.7 to 1.5 52 2.1 1.6 to 2.7 63 2.7 2.1 to 3.4 69 3.2 2.5 to 4.0

RT 32 2.0 1.4 to 2.8 50 3.2 2.4 to 4.2 64 4.1 3.2 to 5.2 69 4.5 3.6 to 5.6

CT1RT 1 0.5 0.1 to 2.5 3 1.4 0.4 to 3.9 3 1.4 0.4 to 3.9 3 1.4 0.4 to 3.9

Treatment, age,30 years

Surgery onlya 11 1.8 1.0 to 3.1 28 4.7 3.2 to 6.6 36 6.3 4.5 to 8.5 42 8.0 5.8 to 10.6

CT 18 1.6 1.0 to 2.5 40 3.6 2.6 to 4.8 46 4.2 3.1 to 5.6 50 4.8 3.6 to 6.3

RT 9 2.5 1.2 to 4.6 16 4.5 2.7 to 7.0 22 6.3 4.0 to 9.1 24 6.9 4.6 to 10.0

CT1RT 0 0 0 2 2.9 0.6 to 9.1 2 2.9 0.6 to 9.1 2 2.9 0.6 to 9.1

Treatment, age$30 years

Surgery onlya 13 1.5 0.9 to 2.5 24 2.9 1.9 to 4.2 26 3.2 2.1 to 4.6 26 3.2 2.1 to 4.6

CT 7 0.5 0.2 to 1.0 12 0.9 0.5 to 1.5 17 1.4 0.9 to 2.2 19 1.7 1.1 to 2.7

RT 23 1.9 1.2 to 2.8 34 2.8 2.0 to 3.9 42 3.5 2.6 to 4.7 45 3.8 2.8 to 5.0

CT1RT 1 0.7 0.1 to 3.6 1 0.7 0.1 to 3.6 1 0.7 0.1 to 3.6 1 0.7 0.1 to 3.6

Histology, all patients

Seminoma 44 1.5 1.1 to 2.0 78 2.7 2.1 to 3.3 97 3.4 2.8 to 4.2 104 3.8 3.1 to 4.6

Nonseminoma 38 1.4 1.0 to 1.9 79 3.0 2.4 to 3.7 95 3.7 3.0 to 4.4 105 4.3 3.5 to 5.1

Histology, age,30 years

Seminoma 13 2.1 1.2 to 3.4 26 4.2 2.8 to 5.9 35 5.8 4.1 to 7.9 38 6.6 4.7 to 8.8

Nonseminoma 25 1.7 1.1 to 2.4 60 4.0 3.1 to 5.1 71 4.9 3.8 to 6.1 80 5.8 4.6 to 7.1

Histology, age$30 years

Seminoma 31 1.3 0.9 to 1.9 52 2.3 1.7 to 2.9 62 2.8 2.2 to 3.5 66 3.1 2.4 to 3.9

Nonseminoma 13 1.1 0.6 to 1.8 19 1.6 1.0 to 2.5 24 2.1 1.4 to 3.1 25 2.3 1.5 to 3.3

NOTE. n refers to the cumulative number of men developing metachronous contralateral TC up until specied follow-up time. Age refers to age at diagnosis ofrst TC, dichotomized on,30 or$30 years.

Abbreviations: CT, chemotherapy; CT1RT, combination of CT and RT; RT, radiotherapy; TC, testicular cancer.

aIncludes men treated with surveillance and men treated with retroperitoneal lymph node dissection in addition to orchiectomy.

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(carboplatin-based, n5332; other CT, n52) was per- formed with no significant change of results (data not shown). Treatment with RT did not affect the second TC risk (HR, 1.10; 95% CI, 0.79 to 1.54).

For each additional CBCT cycle administered, the point estimates for second TC risk decreased, with significantly reduced risks after three (HR, 0.53; 95% CI, 0.29 to 0.97), four (HR, 0.41; 95% CI, 0.25 to 0.66), and more than four cycles (HR, 0.21; 95% CI, 0.07 to 0.66) (Table 4,Fig 2). The hazard of second TC was not significantly different after treatment with adjuvant carboplatin monotherapy (HR, 1.22;

95% CI, 0.62 to 2.39). For each increase of 100 mg/m2 cisplatin, the second TC risk decreased equivalent to the results according to the number of CBCT cycles. The effect on second TC risk was weakened for the dose level of

101-200 mg/m2 when carboplatin was included in the analysis of cumulative platinum doses (AppendixTable A1).

The second TC risk was significantly reduced for those age$30 years atfirst TC diagnosis (HR, 0.47; 95% CI, 0.36 to 0.62). In age-adjusted Cox regression, non- seminoma histology atfirst TC was associated with a de- creased risk of second TC (HR, 0.73; 95% CI, 0.55 to 0.98).

However, compared with seminoma, this association dis- appeared when treatment atfirst TC was included in the model (HR, 0.97; 95% CI, 0.65 to 1.45) (Table 4).

DISCUSSION

In this population-based study, the overall 20-year cu- mulative incidence of a metachronous TC was 4.0% in a well-described cohort with complete information on total treatment burden and a long follow-up time. We demon- strated, to the best of our knowledge for thefirst time, that the risk of a metachronous contralateral TC decreased with each additional CBCT cycle administered, with significantly reduced risks after more than two CBCT cycles.

The overall second TC cumulative incidence of 4% and total SIR of 13.1 found in this study are in accordance with the existing literature.1-7 We found a reduced second TC risk after treatment with CT atfirst TC, and our results lend strong support to the hypothesis that cisplatin reduces the second TC risk.1-3,5 Treatment with RT has not been considered to affect the TC incidence,3,4,12and our results are in agreement with this. Adjuvant infradiaphragmatic RT after seminoma results in a total dose of 0.09-0.32 Gy of scattered radiation to the remaining testicle, which is probably insufficient for eradication of GCNIS if present.23 GCNIS is the precursor of germ cell TC.24If left untreated for 5 years, 50% of patients with GCNIS will develop an in- vasive cancer.25There has not been a tradition to screen for GCNIS in Norway during the study period as it has only been performed in selected high-risk patients.17,26,27 Metastatic TC is highly sensitive to cisplatin. However, cisplatin seems to have a modest but possibly dose- dependent effect on eradication of GCNIS.17,25,28-31 In the present study, we found a strong association between the number of CBCT cycles, cumulative cisplatin dose, and the second TC risk. Our results are in line with the study by Brabrand et al,17who found significantly reduced second TC risk after more than four compared with one to three CBCT cycles or no CT in a study of 61 TCS with biopsy- proven GCNIS in the contralateral testicle. We found no risk reduction after one to two CBCT cycles, which corroborates results from a prospective study on second TC risk after one to two adjuvant CBCT cycles in patients with stage I nonseminoma.26 In contrast to the results from the ran- domized trial by Oliver et al32comparing adjuvant carbo- platin with RT, we found no decrease of second TC risk after treatment with adjuvant carboplatin.

TABLE 3. SIRs for Metachronous Contralateral TC According to Treatment, Age, and Histology at First TC and Follow-up Time

Variable No. of Events SIR 95% CI

Total 218 13.1 11.5 to 15.0

Treatment,rst TC

Surgery onlya 72 16.3 12.9 to 20.5

CT 71 9.1 7.2 to 11.5

RT 72 17.7 14.1 to 22.3

CT1RT 3 8.6 2.8 to 26.7

Age, dichotomized, years

,30 125 13.4 11.2 to 15.9

$30 93 12.8 10.4 to 15.7

Age at diagnosis, years

16-20 9 8.5 4.4 to 16.4

20-30 116 14.0 11.7 to 16.8

30-40 76 13.6 10.9 to 17.0

40-50 14 10.3 6.1 to 17.4

.50 3 9.6 3.1 to 29.6

Histology

Seminoma 107 14.7 12.2 to 17.8

Nonseminoma 111 11.9 9.9 to 14.3

Follow-up time, years

,5 82 17.0 13.7 to 21.2

5-10 75 15.5 12.3 to 19.4

10-15 35 10.4 7.4 to 14.4

15-20 17 8.7 5.4 to 13.9

.20b 9 5.6 2.9 to 10.7

Abbreviations: CT, chemotherapy; CT1RT, combination of CT and RT; RT, radiotherapy; SIR, standardized incidence ratio; TC, testicular cancer.

aIncludes men treated with surveillance and men treated with retroperitoneal lymph node dissection in addition to orchiectomy.

bThe longest time interval betweenrst TC and second TC was 27.1 years.

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The modulating effect of the blood-testis barrier on the intratubular concentration of cytotoxic drugs,33,34possibly in part, explains the need for higher cumulative doses of

cisplatin before effect on GCNIS and the subsequent second TC risk. However, cisplatin undoubtedly has an effect on the testis, demonstrated by the decrease of sperm concentration and quality and the changes of sperm DNA following CBCT.35-37 Furthermore, there seems to be a relationship between the number of CBCT cycles and the recovery of spermatogenesis.36-39 A re- cent publication by Weibring et al40did notfind a long- term reduction of sperm count after one cycle of CBCT.

On the other hand, three or more cycles of CBCT may lead to long-term or permanent impairment of sperm function.36-38

It has been suggested that cisplatin delays rather than reduces the development of a second TC.29,31 In accor- dance with Schaapveld et al,3 our results do not lend support to this hypothesis. On the contrary, we found that there was a longer median time interval betweenfirst TC and second TC after surgery only (7.0 years) than after CT (5.8 years), although not statistically significant. The overall latency of 6.2 years betweenfirst TC and second TC agrees with previous studies.1-3 In the present study, with a very long follow-up time of median 18 years, 72% of second TCs developed within 10 years of follow-up. This is in line with the report of a plateau in incidence after 15-20 years.3,4 However, second TCs may occur late,41 and the longest time interval betweenfirst TC and second TC in our cohort was 27 years.

A polygenic susceptibility, coupled with fetal and early-life environmental factors, is involved in TC development.10,11,42-45

The shared prenatal predisposition of the first and second TC probably accounts for the increased risk of metachronous contralateral TC, and the increased risk in younger versus older men is in turn presumably explained by this.1,46Young age at TC diagnosis has been established as an important risk factor for developing metachronous contralateral TC,1-4,12,13,47and our results are in complete agreement with this. In our study, me- dian age at diagnosis offirst TC was 4.6 years younger in men who later developed a second TC than men with unilateral TC. Furthermore, men age,30 years atfirst TC had more than twice as high 20-year cumulative second TC incidence than those 30 years or older atfirst TC diagnosis.

The current knowledge regarding histology and the risk of metachronous contralateral TC is inconsistent.1,4,7,13,14

Studies conducted in the precisplatin era found a higher risk for metachronous contralateral TC after nonseminoma than after seminoma.4,14In the cisplatin era, some studies concluded with the opposite,7,13 supporting an effect of CBCT.1 We found no associa- tion betweenfirst TC histology and the risk of a second TC when adjusting for age and treatment, which is in line with Andreassen et al.2 Our results suggest that the differences found in histology1,4,7,13,14are in fact caused by the effect of CBCT, as patients with nonseminoma TABLE 4. Age-Adjusted HRs for Metachronous Contralateral TC

According to Treatment Groups, Treatment Intensity, Age, and Histology at First TC

Variable HR 95% CI P

Treatment

Surgery only 1 Ref Ref

CT 0.55 0.40 to 0.76 <.001

RT 1.10 0.79 to 1.54 .580

CT1RT 0.50 0.16 to 1.57 .233

No. of CBCT cycles

Surgery only 1 Ref Ref

1 1.01 0.52 to 1.96 .983

2 0.74 0.40 to 1.36 .332

3 0.53 0.29 to 0.97 .040

4 0.41 0.25 to 0.66 <.001

.4 0.21 0.07 to 0.66 .008

Carboplatin, adjuvanta 1.22 0.62 to 2.39 .565 RTeld

Surgery only 1 Ref Ref

L-Field 1.17 0.78 to 1.62 .521

Para-aortal 0.75 0.34 to 1.64 .468

RT dose forrst abdominal RT-eld, Gy

Surgery only 1 Ref Ref

20-29 1.24 0.77 to 1.98 .383

30-39 1.04 0.70 to 1.55 .832

$40 1.17 0.50 to 2.70 .721

Age at diagnosis,byears

,30 1 Ref Ref

$30 0.47 0.36 to 0.62 <.001

Histology Age-adjusted

Seminoma 1 Ref Ref

Nonseminoma 0.73 0.55 to 0.98 .034

Multivariablec

Seminoma 1 Ref Ref

Nonseminoma 0.97 0.65 to 1.45 .883

NOTE. Signicant results marked with bold. Age refers to age at diagnosis ofrst TC, dichotomized on,30 or$30 years.

Abbreviations: CBCT, cisplatin-based chemotherapy; CT, chemotherapy; CT1RT, combination of CT and RT; Gy, gray; HR, hazard ratio; Ref, reference; RT, radiotherapy; TC, testicular cancer.

aCarboplatin monotherapy, carboplatin in adjuvant setting for stage I seminoma.

bNot age adjusted.

cAdjusted for treatment in addition to age.

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are more often treated with CBCT than patients with seminoma.

In a recent review by Zequi et al,4860.4% of metachronous contralateral TCs had a seminoma histology. This is in line with the present study in which 72% of the second TCs were seminomas. The abundancy of seminoma histology of second TCs is probably caused by age.18

In our study, the majority (84%) of second TCs were di- agnosed as clinical stage I, and this correlates with the results published in the review by Zequi et al48(73.3% in stage I). Our even higher proportion diagnosed in stage I might be a result of robust follow-up procedures, central- ized treatment of TC in Norway, and the risk-adapted bi- opsy strategy of the contralateral testicle.27,49

Important strengths of our study include the consideration of a nationwide cohort, the completeness of cancer inci- dence rates of the CRN,18and the complete information on treatment burden in a large and unselected study cohort with a long follow-up time. The risk-adapted treatment

strategy in clinical stage I disease recommended by SWENOTECA has made it possible to compare adjuvant CT with the surveillance strategy.21

The lack of information regarding GCNIS and risk factors for TC, such as family history of TC, history of cryptorchidism, or infertility, are potential limitations. Tissue samples available for genetic analyses could have been of particular interest.

In conclusion, we found a strong association between the number of CBCT cycles and the subsequent risk of a metachronous contralateral TC. Patients with metastatic unilateral TC might appreciate information on the signifi- cant risk reduction of second TC after treatment with CT.

Although most second TCs develop within 10 years after diagnosis of thefirst TC, they may develop after more than 20 years. It is important that TCS are aware of this risk and that the importance of regular lifelong self-examination is emphasized.

AFFILIATIONS

1Department of Oncology, University Hospital of North Norway, Tromsø, Norway

2Department of Clinical Medicine, UiT, The Arctic University of Norway, Tromsø, Norway

3Department of Research and Innovation, Møre and Romsdal Hospital Trust,Alesund, Norway˚

4Department of Registration, Cancer Registry of Norway, Oslo, Norway

5Department of Oncology, Haukeland University Hospital, Bergen, Norway

6Department of Oncology,Alesund Hospital,˚ Alesund, Norway˚ 1

2 3 4 5 6 7 8 9 10

Proportion Diagnosed With Second TC, %

> 4 cycles 4 cycles 3 cycles 2 cycles 1 cycle

277 203 187 153 123 71 19

752 904 850 640 479 298 178

270 410 365 234 147 98 68

269 305 284 185 102 29 15

158 205 151 77 18 4 2

2,042 1,379 1,201 794 473 305 162

Surgery only N at risk:

0 5 10 15 20 25 30

Follow-Up Time (years)

Surgery only 1 cycle 2 cycles 3 cycles 4 cycles

> 4 cycles

FIG 2. Proportion diagnosed with metachronous contralateral TC by follow-up time and the number of cisplatin- based chemotherapy cycles, adjusted for age at TC diagnosis. The risk table presents the crude number of individuals by follow-up time. TC, testicular cancer.

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7Department of Oncology, Oslo University Hospital, Oslo, Norway

8The Cancer Clinic, St. Olavs University Hospital, Trondheim, Norway

9Department of Clinical and Molecular Medicine, The Norwegian University of Science and Technology, Trondheim, Norway

10Department of Community Medicine, UiT, The Arctic University of Norway, Tromsø, Norway

11Institute of Clinical Medicine, University of Oslo, Oslo, Norway

CORRESPONDING AUTHOR

Ragnhild Hellesnes, MD, Department of Oncology, University Hospital of North Norway, N-9038, Tromsø, Norway; e-mail: ragnhild.hellesnes@

unn.no.

DISCLAIMER

The study has used data from the Cancer Registry of Norway. The interpretation and reporting of these data are the sole responsibility of the authors, and no endorsement by the Cancer Registry of Norway is intended nor should be inferred.

PRIOR PRESENTATION

Presented in part at the ESMO Virtual Congress 2020, Science Weekend, September 19-21, 2020.

SUPPORT

Supported by grants from Helse Nord RHF (grant no. SPF1230-15).

AUTHORS’DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Disclosures provided by the authors are available with this article at DOI https://doi.org/10.1200/JCO.20.02713.

AUTHOR CONTRIBUTIONS

Conception and design:Ragnhild Hellesnes, Torgrim Tandstad, Hege S.

Haugnes

Financial support:Hege S. Haugnes

Provision of study materials or patients: ´Asa Karlsdottir, Helene F. S.

Negaard, Torgrim Tandstad, Sophie D. Foss˚a, Hege S. Haugnes Collection and assembly of data:Ragnhild Hellesnes, ´Asa Karlsdottir, Øivind Kvammen, Helene F. S. Negaard, Torgrim Tandstad, Sophie D.

Fossa, Hege S. Haugnes˚

Data analysis and interpretation:Ragnhild Hellesnes, TorAge Myklebust,˚ Roy M. Bremnes, Øivind Kvammen, Helene F. S. Negaard, Torgrim Tandstad, Tom Wilsgaard, Sophie D. Fossa, Hege S. Haugnes˚ Manuscript writing:All authors

Final approval of manuscript:All authors

Accountable for all aspects of the work:All authors

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13. Che M, Tamboli P, Ro JY, et al: Bilateral testicular germ cell tumors: Twenty-year experience at M. D. Anderson Cancer Center. Cancer 95:1228-1233, 2002 14. Osterlind A, Berthelsen JG, Abildgaard N, et al: Risk of bilateral testicular germ cell cancer in Denmark: 1960-1984. J Natl Cancer Inst 83:1391-1395, 1991 15. Einhorn LH, Donohue J: Cis-diamminedichloroplatinum, vinblastine, and bleomycin combination chemotherapy in disseminated testicular cancer. Ann Intern

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16. Feldman DR, Bosl GJ, Sheinfeld J, et al: Medical treatment of advanced testicular cancer. JAMA 299:672-684, 2008

17. Brabrand S, Fossa SD, Cvancarova M, et al: Probability of metachronous testicular cancer in patients with biopsy-proven intratubular germ cell neoplasia depends onrst-time treatment of germ cell cancer. J Clin Oncol 30:4004-4010, 2012

18. Larsen IK, Møller B, Johannesen TB, et al: Cancer in Norway 2018Cancer Incidence, Mortality, Survival and Prevalence in Norway. Oslo, Norway, Cancer Registry of Norway, 2019

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21. Cohn-Cedermark G, Stahl O, Tandstad T, et al: Surveillance vs. adjuvant therapy of clinical stage I testicular tumorsA review and the SWENOTECA ex- perience. Andrology 3:102-110, 2015

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37. Lampe H, Horwich A, Norman A, et al: Fertility after chemotherapy for testicular germ cell cancers. J Clin Oncol 15:239-245, 1997

38. Brydoy M, Fossa SD, Klepp O, et al: Paternity and testicular function among testicular cancer survivors treated with two to four cycles of cisplatin-based chemotherapy. Eur Urol 58:134-140, 2010

39. Pont J, Albrecht W: Fertility after chemotherapy for testicular germ cell cancer. Fertil Steril 68:1-5, 1997

40. Weibring K, Nord C, Stahl O, et al: Sperm count in Swedish clinical stage I testicular cancer patients following adjuvant treatment. Ann Oncol 30:604-611, 2019˚ 41. Dieckmann K-P, Anheuser P, Sattler F, et al: Sequential bilateral testicular tumours presenting with intervals of 20 years and more. BMC urology 13:71, 2013 42. Rajpert-De Meyts E, McGlynn KA, Okamoto K, et al: Testicular germ cell tumours. Lancet 387:1762-1774, 2016

43. Lan JT, Bagrodia A, Woldu S, et al: New insights into germ cell tumor genomics. J Androl 7:507-515, 2019

44. Facchini G, Rossetti S, Cavaliere C, et al: Exploring the molecular aspects associated with testicular germ cell tumors: A review. Oncotarget 9:1365-1379, 2018 45. Wang Z, McGlynn KA, Rajpert-De Meyts E, et al: Meta-analysis ofve genome-wide association studies identies multiple new loci associated with testicular

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46. Harland SJ, Cook PA, Fossa SD, et al: Intratubular germ cell neoplasia of the contralateral testis in testicular cancer: Dening a high risk group. J Urol 160:

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47. Theodore C, Terrier-Lacombe MJ, Laplanche A, et al: Bilateral germ-cell tumours: 22-year experience at the Institut Gustave Roussy. Br J Cancer 90:55-59, 2004

48. Zequi Sde C, da Costa WH, Santana TB, et al: Bilateral testicular germ cell tumours: A systematic review. BJU Int 110:1102-1109, 2012

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n n n

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AUTHORS’DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Metachronous Contralateral Testicular Cancer in the Cisplatin Era: A Population-Based Cohort Study

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted.

Relationships are self-held unless noted. I5Immediate Family Member, Inst5My Institution. Relationships may not relate to the subject matter of this manuscript.

For more information about ASCOs conict of interest policy, please refer towww.asco.org/rwcorascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

No potential conicts of interest were reported.

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APPENDIX

Declined to participate (n = 23, 0.38%)

Dataset used as basis for collection of clinical data (n = 6 057, 95.3%)

Males diagnosed with germ cell TC in the NCR (coded with localization ICD-7 178.x) between 01/01/1980-12/31/2009

(N = 6 354)

Dataset used as basis for information letter (n = 6 080, 95.7%)

Cohort for the analysis of metachronous contralateral TC = study population

(n = 5 620, 88.4%)

Cohort of TCS with complete clinical data (n = 5 724, 90.1%)

(n = 180) (n = 24) (n = 4) (n = 66) Extragonadal localization (ICD-7 178.4)

Localization ductus deferens or funicle (ICD-7 178.3) Localization epididymis (ICD-7 178.2)

Age < 16 years

Excluded (n = 274, 4.3%)

Previous diagnosis of non-TC cancer TC before 1980

Extragonadal localization Clinical data missing

Other histology than GC cancer Treated abroad

Clincial diagnosis only/histology not performed Other causes

Synchronous non-TC diagnosis

(n = 58) (n = 27) (n = 51) (n = 55) (n = 99) (n = 11) (n = 11) (n = 2) (n = 19) (n = 333 5.5%) Excluded

Excluded from the present study (n = 104, 1.8%) due to the following events < 2 months after first primary TC-diagnosis:

♦ Synchronous bilateral TC (n = 61)

Death (n = 35 [of which 7 were also diagnosed with synchronous bilateral TC])

Emigration (n = 8 [of which 3 were also diagnosed with bilateral TC])

FIG A1. Flowchart presenting the study cohort. GC, germ cell; ICD-7, International Classication of Diseases Version 7; NCR, the Norwegian Cancer Registry; TC, testicular cancer; TCS, testicular cancer survivors.

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TABLE A1. Age-Adjusted HRs for Metachronous Contralateral TC According to Cumulative Cisplatin, Platinum, and Bleomycin Doses at First TCa

Chemotherapy Dose HR 95% CI P

Cumulative cisplatin dose, mg/m2

Surgery only 1 Reference Reference

1-100 1.01 0.52 to 1.96 .984

101-200 0.74 0.40 to 1.36 .331

201-300 0.53 0.29 to 0.98 .043

301-400 0.43 0.27 to 0.70 .001

.400 0.14 0.03 to 0.52 .004

Carboplatin 1.15 0.62 to 2.12 .667

Cumulative total platinum dose, mg/m2b

Surgery only 1 Reference Reference

1-100 1.01 0.52 to 1.96 .984

101-200 0.91 0.56 to 1.47 .697

201-300 0.53 0.29 to 0.99 .045

301-400 0.46 0.29 to 0.72 .001

.400 0.12 0.03 to 0.50 .003

Cumulative bleomycin dose, IU

Surgery only 1 Reference Reference

1-100,000 0.92 0.50 to 1.70 .789

100,001-200,000 0.55 0.26 to 1.14 .107

200,001-300,000 0.46 0.30 to 0.69 <.001

.300,000 0.29 0.07 to 1.19 .086

Chemotherapy without bleomycin 0.84 0.47 to 1.50 .550

NOTE. Signicant results marked with bold.

Abbreviations: HR, hazard ratio; TC, testicular cancer.

aWhen analyzing the effect of cumulative doses, the proportional hazard assumption was violated for some treatment groups. Wetted new models with an interaction effect between follow-up time and the selected treatment groups and compared modelt using BIC. In all cases, the bestt was provided by the simple model without interaction effects, and hence, the results from these are presented.

bCumulative total platinum doses contain cumulative doses of cisplatin and/or carboplatin. For carboplatin, the corresponding cisplatin-equivalent doses were estimated by dividing the carboplatin doses by four (Ozols Cancer Treat Rev. 1985).

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